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LATE EFFECTS after Allogeneic Stem Cell Transplantation

LATE EFFECTS after Allogeneic Stem Cell Transplantation. ~60,000 transplants/year. 30000 autotransplants. Transplants. 25000 allotransplants. Pasquini MC, Wang Z. CIBMTR Newsletter, 2009. SUM10_4.ppt.

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LATE EFFECTS after Allogeneic Stem Cell Transplantation

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  1. LATE EFFECTS after Allogeneic Stem Cell Transplantation

  2. ~60,000 transplants/year 30000 autotransplants Transplants 25000 allotransplants Pasquini MC, Wang Z. CIBMTR Newsletter, 2009 SUM10_4.ppt

  3. Improving One-Year Survival after a Myeloablative Conditioning Regimen for Acute Leukemias in any Remission, CML or MDS, Age <50 Years, 1988-2007, by Year of Transplant and Graft Source 100 HLA-matched sibling URD 80 60 One-Year Survival, percent Better supportive care 40 Gentler conditioning 20 Improved mgmt of GVHD 0 1988- 1991 1992 1993 1994 1995 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 1990 Pasquini MC, Wang Z. CIBMTR

  4. Long-term Follow Up after SCT • First successful transplants – late 1960’s and early 1970’s • Improvements in SCT outcomes resulted in a larger number of cure patients • >30,000 Patients >5 years from SCT • Increasing annually • As they age, more attention must be paid to long-term complications

  5. Long term stem cell allotransplant survivors are a growing population Approximate number of allotransplants in the last 30 years 450,000 50% Average survivorship per annum 225,000 Projected number of new long term survivors generated 2020 (conservative) Assume 5% increase / annum 10 years 320,000 Assume average survival over the decade 80% 255,000 Estimated worldwide allogeneic transplant survivors by 2020 ~ 500,000 Estimated US population of allogeneic transplant survivors by 2020 ~140,000 How I treat late effects in adults after allogeneic stem cell transplantation. Blood 2011 Semin Hematol 2012

  6. Long-term Survival after HCT • CIBMTR study of 10,632 allogeneic HCT recipients surviving ≥ 2 years in remission (median follow-up 9 years) Overall survival Non-relapse mortality J Wingard et al, JCO 2011 ; 29: 2230

  7. CHECKLIST DISEASE- restaging, TKIs/ hypomethylating agents, etc * cGVHD- activity versus sequelae* IMMUNE RECONSTITUTION- reimmunization status, infection risks* SEQUELAE-pulmonary *, endocrine*, ophthalmic*, fertility*, iron*, bone health*, cognition & mental health*, renal*, sexual dysfunction* GENERAL HEALTH- Secondary cancers * *Common and serious*Uncommon but life threatening *Common but not life threatening

  8. Timelines for post SCT complications Years 1 3 5 10 20 15 A-GVHD Thyroid failure Male fertility QOL Early TRM Cataract surgery Bone loss / premature ageing Cardiovascular / Pulmonary C-GVHD Relapse Viral reactivation Second cancers

  9. What goes wrong: the next 3 years • Graft Failure • Relapse • Transplant-related complications- cGVHD • Hepatic, skin, musculoskeletal, BOOP • Limited lifestyle • Immunodeficiency • VZV, Pneumococcus/ hemophilus etc • Conditioning regimen-related problems

  10. What goes wrong: the next 30 years • Late effects • Metabolic complications • Pulmonary complications • Bone loss/ AVN • Delayed immune reconstitutions • Renal complications • IQ, cognitive problems • Second malignancies • Lifestyle • Lifespan • Premature aging?

  11. Immune dysfunction underpins many late effect complications Conditioning regimen Pre-transplant/genetic predisposition Gonadal failure Iron Overload Osteoporosis Pulmonary failure Second cancers Thyroid failure Endocrine Failure Cataracts Infection cGVHD Immune dysfunction

  12. Immunity and Infections

  13. Late Infections CIBMTR

  14. Delayed immune recovery

  15. Defects in humoral immunity • Hypogammaglobulinemia is common • Normal or near normal values do not necessarily mean protective level of IgG • Apparently normal IgG levels may obscure low IgG2 and IgG4 needed to clear encapsulated organisms • Low secretary IgA • Increase susceptibility to conjunctivitis, sinusitis, bronchitis, etc. • Loss of splenic function • May require long-tem prophylaxis with antibiotics designed to prevent pneumococcal disease • Increasingly problematic as the bacteria develop antimicrobial resistance

  16. Defects in cellular immunity • Varicella-zoster reactivation is 20-50% • ~ 10% of cases → pain without rash • Cytomegalovirus • First 3-4 months after SCT • Late infections may be increasing with pre-emptive therapy • PCP • >1 year after SCT • Continued immunosupression requires sustained prophylaxis • Daily bactrim prevent PCP and reduce the risk of pneumococcal sepsis and toxoplasmosis

  17. Infection- pneumococcal sepsis after SCT higher probability of pneumococcal infection among allograft recipients • No pneumococcal vaccine • PCN or Ery (compliance • not monitored) • Pneumonia 16 • Bacteremia alone 19 • With meningitis 3 • With pneumonia 3 • 23% mortality Kulkarni et al. Blood 2000;95:3683-6

  18. Infection- pneumococcal sepsis after SCT Significantly higher risk for pneumococcal sepsis among allograft recipients with chronic graft versus host disease Kulkarni et al. Blood 2000;95:3683-6

  19. Antimicrobial prophylaxis • Antifungal- if on systemic IST, particularly steroids, iron overload. • ACV- for VZV at least 1 year post cessation of IST. Varicella-zoster reactivation is 20-50%. ~ 10% of cases → pain without rash. • PCN- vs encapsulated (while on IST) • PCP prophy- At least 6 months post cessation of IST.

  20. Vaccination schedule CDC/ASBMT guidelines 2012. NIH BMT CONSORTIUM 2013

  21. Updated vaccination recommendations ACIP recommendations for pneumococcal vaccines (June 2012) - Fifty percent of invasive pneumococcal disease cases were caused by serotypes contained in PCV13 (Prevnar); an additional 21% were caused by serotypes only contained in PPSV23 (Pneumovax) (CDC, unpublished data, 2011). - New vaccination guidelines recommend three doses of Prevnar followed by one dose of Pneumovax in allogeneic transplant recipients. CDC 2012; How I Treat – Compendium

  22. Cardiovascular complications Events: CAD, CVA >>PAD Magnitude: CVD is 3-fold higher than sibling controls Risk factors: dyslipidemia-driven Etiology: XRT, steroids, endocrinopathy Management: address modifiable factors (lipids, DM, HTN, smoking) Rovo et al. Semin Hematol 2012 Griffith et al. Dyslipidemia after allo-HCT. Blood 2010

  23. Dyslipidemia in 44% and 52% at 5 and 10 years post-SCT. • 23% of 5-year survivors met the ATPIII threshold for dyslipidemia treatment. • Increased prevalence of hypertension (p<0.001), diabetes (p=0.018) and BMI (p=0.044) compared to baseline. • The Framingham general CV risk score (FGCRS) in males at 5 years post-SCT projected a doubling (10.4% vs. 5.4%) in the 10-year risk of cardiovascular events. • Elevated CVRF stabilized between 5 and 10 years post-SCT but . Pophali, et al. Exp Hematol 2013.

  24. Griffith et al. Dyslipidemia after allo-HCT. Blood 2010

  25. Pulmonary complications Cumulative pulmonary injury 30-60% Impact of cGVHD on the time to PFT decline . Biol Blood Marrow Transplant. 2006;12:1261-9.

  26. Bronchiolitis Obliterans Syndrome • Facts • Insidious, 2-5years. • ~15% of cGVHD. • high morbidity and mortality • In lung transplantation, affects 50%. • Small airway narrowing 45% of terminal bronchioles lost before impacting • FEV1 or FEV1:FCV ratio. Probably irreversible once symptomatic. • Diagnostic criteria: • decreased FEV1 <75%, AND FEV1/FVC ratio of <0.7 on PFT • RV>120% OR air trapping on computed tomography or lung biopsy • absence of acute respiratory infection AND • cGVHD in an additional organ system if no histologic evidence of BOS can be demonstrated. Sengsayadeth et al. Biol Blood Marrow Transplant. 2012;18:1479-87

  27. Prevention & Therapeutic Strategies • Aggressive GVH prophylaxis (ATG) in patients with pre-transplant abnormal PF- goal to prevent cGVHD (BMT 2013 in press). • Inhaled steroids • Azithromycin • FAM (fluticasone/azithro/monteleukast) • Investigational therapy- inhaled cyclosporine • Lung transplantation Sengsayadeth et al. Biol Blood Marrow Transplant. 2012;18:1479-87

  28. Bone health- Avascular necrosis Incidence 4-19% Hips > knees, ankles or shoulder Sometimes infected. Often excruciating. Median at 2 years IST use, mainly steroids (ALL, female) MRI – most sensitive + extent of involvement Mx: Conservative- reduce wt bearing. Surgical- core decompression-> -> joint replacement No role for statins or bisphosphonates! Blood and Marrow Transplantation Long Term Management: Prevention and Complications Nov 2013

  29. Bone health- BMD loss Definitions: Osteopenia (T-score between -1.5 and -2.5) and osteoporosis (<-2.5 or fragility frx) Features: Bone loss occurs in 50-60% • ~ 20% develop osteoporosis • Children >> adults (but no fractures) • Trabecular bone (hip & spine) are more susceptible. • Commonest fracture site is femoral neck. • Extremely rapid in the first 4 months (~7-10 years of normal aging) Risk factors: Steroids, hypogonadism, Vit D (diet, renal), RANK-L, inactivity Screening: DEXAs, VitD levels. Management: Calcium (1,200 mg daily)/ vitamin D (1,000 IU/d), exercise, bisphosphonates (individualize- risk of osteonecrosis, drug holiday reqd after 3-5 yrs), HRT for all females at risk, role of androgens is unknown. Denosumbab is untested. McClune et al. Semin Hematol 2012 Blood and Marrow Transplantation Long Term Management: Prevention and Complications Nov 2013

  30. Bone Loss in Patients post SCT BBMT. 2007

  31. Proposal for BMT CTN Trial: BMT-CTN (SOSS)Schema Allogeneic HCT, adults, 100 ± 30 days post-HCT Femur neck T-score < -2.5 DEXA scan Treat Femur neck T score ≥ -2.5 RANDOMIZE Reclast (1 dose) + Ca/Vit D Placebo (1 dose) + Ca/Vit D DEXA scan at 1 yr post-HCT

  32. Endocrine dysfunction DM: risk is 3x that of sibling controls. cGVHD, TBI, steroids. HbA1c is unreliable. Oral hypoglycemics often CI. Male hypogonadism: • Testosterone producing Leydig cells less damaged than sperm producing Sertoli. • Recovery of spermatogenesis in 50-90% of non-TBI and ~ 25% of TBI survivors. • Supplement testosterone very selectively -low morning total testosterone level AND reduced libido/bone mass. Monitor LFTs, PSA and Hct. Thyroid: • ~ 30% of pediatric patients followed long term – TBI & cGVHD. • TSH elevations are initially subclinical. Rx- lifelong supplementation. • Thyroid adenomas and carcinomas may occur at higher rates than expected (XRT) Adrenal Insuff: • Overt or ACTH challenge. High prevalence (19 of 20 in one series). QOD steroids. Pituitary: • Growth failure, central hypogonadism or hypothyroidism. • TBI, young age at BMT • 40/141 children failed to achieve normal adult height. • Growth charts Gunasekaran et al. Semin Hematol 2012

  33. Thyroid functions in long term survivors Prolonged IST and hypothyroidism Age and overt hypothyroidism BBMT, 2009

  34. Delayed chronic kidney disease Estimates of CKD in HCT survivors vary from 13% to 66% for adults and 62% in children. Often delayed up to 10 years post transplant. CKD defined as a sustained elevation of serum creatinine (GFR < 60 mL/min/1.73 m2) for 3 months or longer Mx: HTN, Renal fxn, exclude obstructive uropathies, renal biopsies for etiology. Abboud et al. Semin Hematol 2012

  35. Choi et al. Cancer 2008;113:1580-7

  36. Ophthalmic #1 cGVHD #2 Cataracts Others- xerophthalmia w/o cGVHD, corneal ulcers, glaucoma, CMV retinitis, fungal endophthalmitis, donor allergy. The cumulative incidence of major ocular complications- 13%. cGVHD Lacrimal, conjunctival, lids, cornea. Sicca Rx: Artificial tears tpical CSA/steroidsplugs punctalcautery autologous serum Premature Cataracts 23% in peds Steroids and TBI (lens shielding) Rx: aggressive management of dry eyes Blood and Marrow Transplantation Long Term Management: Prevention and Complications Nov 2013

  37. Female long term survivors • cGVHD- vulvar and vaginal. • 25-50%. Underreported. • Vulvar starts in 1st year but vaginal • may present several yrs later. • Severest form- hematocolpos. • Regular mandatory GYN • screening reduces surgery. • Rx: Topical IST, estrogens, • dilators. • HRT and contraception • HPV-related cervical dysplasia • Infertility • Sexual health. • Hypogonadism. Shanis et al. Semin Hematol 2012

  38. Iron Overload 30-60%, easy to overlook. Sole pathologic finding in one third of liver biopsies. Effects: Organ dysfunction, ROS, (?) Invasive fungi. Liver accumulates iron but most significant sequelae are cardiac and endocrine. Screen by ferritin, but confirm by MRI (has replaced LIC). Accumulating data showing “associations” w worse prognosis. Rx: Phlebotomy once no longer anemic. Chelation is controversial and toxic but one study showed benefit by reducing relapse (!). Brissot et al. Semin Hematol 2012

  39. Figure 1. Inflammation Sensitivity and specificity of R2-LIC measurements to biopsy LIC Elevated Ferritin after HCT* Infection GVHD Iron overload R2 MRI liver- LIC** (Ferriscan) 1. Olivieri NF, Brittenham GM. Blood. 1997;89:739-61. 2. St Pierre TG, et al. Blood. 2005;105:855-61. • Therapeutic and preventive strategies: • Iron depletion • Chelation post-HCT-ongoing clinical trials • Phlebotomy- if not anemic Iron overload St Pierre TG, et al. Blood. 2005;105:855-61. * Elevated Ferritin Iron overload: transfusion, dyserythropoiesis, associated genetic factors (HEF mutations) Non iron overload etiology: inflammation (GVHD, infections, radiation), metabolic syndrome (immunosuppression), hepatitis (viral, drugs, GVHD, radiation), associated ETOH usage **LIC predicts body iron stores, changes in LIC show changes body iron with chelation therapy, calculate iron balance, predicts risk of hepatic complications and risk of extra-hepatic complications Blood. 2013 Aug 29;122(9):1539-41

  40. Previous exposures (HPV infection) Primary therapy (chemotherapy/RT) Conditioning regimen (TBI) Graft-vs-host disease DIAGNOSIS Pre-HCT HCT Post-HCT Genetic predisposition Age & Gender Lifestyle factors New Secondary Solid Cancers • Latency period of 3-5 yrs, incidence increases with time • ~1-2% at 5 yrs, ~2-6% at 10 yrs, ~4-15% at >15 yrs Risk factors for second solid cancers Bone Marrow Transplant. 2013;48:363-8 Majhail et al . Bone Marrow Transplant 2012 Socié & Rizzo. Semin Hematol 2012 Clin Cancer Res. 2009;15:2219-21 Rizzo JD. Blood 2009;113:1175-83

  41. Second malignancies in long-term survivors • Cumulative - 11.5 ± 2.3% at 15 years • Most frequent cancers • Skin • Oral cavity & larynx • Cervix/ uterine • Risk factors: • Older age • cGVHD Kolb et al Ann Intern Med 1999;131:738-44

  42. Second malignancy Cumulative probability of developing a malignant neoplasm as a function of time after bone marrow transplantation Expected Kolb et al Ann Intern Med 1999;131:738-44

  43. Second malignancies in long-term survivors • Cumulative prob – 6.1 ± 1.5% at 10 years • Most frequent cancers • Liver cancer (HCV related) • Oral cavity • Cervical cancer • Risk factors: • cervical cancer - older age • skin cancer - cGVHD Bhatia et al. J Clin Oncol 2001;19:464-71.

  44. Most common second cancers are linked to HPV • Cervical cancer • HPV-16, 18 cause ~70% of anogenital cancers • Oropharyngeal squamous cell cancer • > 5000 cases, 35.6% HPV+ (Kreimer et al 2005) • Of these, 86.7% HPV-16 • HPV-16 in 72% of cases (D’Souza et al NEJM 2007) • HPV-16 precedes cancer by 10 years (Mork et al NEJM 2001) • Skin cancer • HPV in 70-90% cutaneous SCC (Dermatol Surg 2004) • HPV SCC in renal transplant- 3 drugs > 2 IMS Socié & Rizzo. Semin Hematol 2012 Clin Cancer Res (review). 2009;15:2219-21 Rizzo JD. Blood 2009;113:1175-83

  45. HPV related cervical dysplasia • 35 (92.1%) had cervical cytology • 3 less than 18 years • Abnormal cervical cytology - 14 (40%) • 12 (34%) with HPV squamous intraepithelial lesions • High grade 8 (23%) • Low grade 4 (11%) • 2 ASCUS and HPV high/low risk subtype negative • Median time to abnormal: 51 months (range 17-153) • Median age: 42 years (range 19-62) • Only 3 patients < 42 year with dysplasia Biol Blood Marrow Transplant. 2008;14:1072-5

  46. HPV related cervical dysplasia • Factor associated with cervical dysplasia • Extensive cGVHD on prolonged immunosuppressive therapy (OR 5.4, p=0.01) Biol Blood Marrow Transplant. 2008;14:1072-5

  47. Second malignancy Pattern of risk for second malignancy after SCT Deeg et al. Blood 1998;91:1833-44

  48. Screening Recommendations * Adapted from Children’s Oncology Group guidelines and EBMT/CIBMTR/ASBMT guidelines- 2012/ 2013 † Similar to American Cancer Society recommendations for general population cancer screening

  49. Screening Needs to be Individualized RISKS ARE NOT SAME 10 year old with Hodgkin’s lymphoma treated with autologous HCT 60 year old with AML treated with allogeneic HCT and has GVHD

  50. Updated vaccination recommendations HPV Vaccine Recommendations - The quadrivalent HPV vaccine is approved for males and females aged 9-26 years to prevent HPV-related diseases including cervical, vulvar, and vaginal cancers and precancers in females, as well as anal cancers and precancers and genital warts in both females and males. - We recommend vaccination starting at ≥12 months post- transplantation, regardless of prior sexual activity and exposure to carcinogenic strains. How I Treat – Compendium

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